16-halo estrogens



3,153,065 16-HALO ESTRUGENS Albert Bowers and Pierre Crabbe, MexicoCity, Mexico,

assignors, by mesne assignments, to Syntex Corporation, a corporation ofPanama No Drawing. Filed Mar. 1, 1962, Ser. No. 176,772 20 Claims. (Cl.260-39745) The present invention relates to novelcyclopentanophenanthrene derivatives and to a process for the productionthereof.

More particularly the present invention relates to novel 16-halo-A-estratetraene derivatives.

The novel compounds of the present invention are rep- I resented by thefollowing formulas:

In the above formulas R represents hydrogen, lower alkyl or ahydrocarbon carboxylic acyl group of less than 12 carbon atoms; Rrepresents hydrogen or a hydrocarbon carboxylic acyl group of less than12 carbon atoms; R represents hydrogen, lower alkyl, lower alkenyl, or

lower alkynyl and X represents halogen. The wavy line at -16 indicatesthat the substituent is in the or or B position. The acyl groups arederived from hydrocarbon carboxylic acids containing less than 12carbonatoms which may be saturated or unsaturated, of straight, branched,cyclic or cyclic-aliphatic chain, aromatic and may be substituted byfunctional groups such as hydroxy, alkoxy containing up to carbon atoms,acyloxy containing up to 12 carbon atoms, nitro, amino or halogen.

' Typical ester groups are the acetate, propionate, enantion:

. t i m I (j BO I. RO H.

United States Patent 0 "cc Patented Oct. 13, 1964 In the above formulasR, R R and X have. the same meaning as previously defined and Acrepresents the acyl group, preferablythe acetyl radical.

In practicing the process outlined above the starting compound (I) whichis selected from the group consisting of A dehydroestrone, the 3-loWeralkyl ethers or the 3-acylates thereof, are treated with isopropenylacetate in the presence of p-toluenesulfonic acid at reflux temperaturefor a period of time of the order of 24 hours to give the corresponding17-enol ester (11). This enol ester upon treatment with approximately 1molar equivalent of an N-(chloro or bromo) amide such as N-(chloro orbromo) succinimide yields the corresponding 16achloroor b-romo-17-ketocompound (III: X=chlorine or bromine); The same enol ester When treatedwith an N-iodo-amide, such as N-iodo succinimide gives the corresponding16a and 16,8-iodo-l7-keto compounds (III and IV: X=iodine).

The 16fi-fluoro derivative (IV: X:fiuorine) are obtained from thecorresponding 16a-iodo compounds by treatment with silver fluoride in'asuitable solvent such as acetonitrile. The 16 fluoro v derivatives (III:X=fluorine) are produced by treatment of the corresponding 17-enolesters (II) with perchloryl fluoride in a suitable solvent such asdime'thylformamide. The 16oc-i0d0 and 16a-bromo compounds, upon reactionwith alkali metal halides, preferably'lithium halides in a suitablesolvent such as dimethylformarnide Y afford the corresponding l6/3-haloderivatives '(IV).

The 16u-halo and 16B-ha1o-17-ketones (III and IV) are reduced,preferably with sodium borohydride, to produce the correspondingl6-halo-l7fl-alcohols (V:R '=R =H) The same 16-halo 17-ketones (III andIV) upon reaction with a lower alkyl magnesium halide, such as'methylmagnesium bromide, yield the corresponding 16-halo-17aloweralkyl-17fi-alcohols (V:R ,,=H; R =lower alkyl).

The aforementioned 16-halo-17-ketones (III and IV) upon treatment with al-lower alkyne such as acetylene in the presence of potassiumt-amyloxide yield the corresponding 16halO-170t-1OWCIalkynyl-l7B-alcohols .,(V:R =I-l; R =lower alkynyl) which arehydrogenated 3 in the presence of a suitable catalyst such as 2%palladium-on calcium carbonate, to produce the corresponding17a-lower-alkenyl derivatives (V:R =H, R =lower alkenyl).

The secondary 17,8-alcohols of the present invention (V:R =R :H) areconventionally acylated in pyridine with an acylating agent such as ananhydride derived from a hydrocarbon carboxylic acid of the hereinbeforedefined type, to produce the corresponding 17,8-acylates The tertiaryfill-alcoholsof the present invention (V:R =l-I, R =lower aliphatichydrocarbon) are conventionally acylated in the presence ofp-toluenesulronic acid with an acylating agent, e.g., acetic anhydrideor propionic anhydride, to give the corresponding17a-substituted-17fi-acylates (V:R =acyl, R =lower aliphatichydrocarbon).

The following specific examples serve to illustrate, but are notintended to limit the scope of the present invention:

Example I I A mixture of 1.2 g. of A -dehydroestrone-3-methyl ether(Magerlein et al. I. Am. Chem. $00., 80, 2220 (1958)),20 cc. ofisopropenyl acetate and 60 mg. of paratoluenesulfonic acid was refluxedusing an air condenser so that approximately 2 cc. of solvent distilledoil over a period of 30 minutes.

A water-cooled condenser was then substituted for the air condenser andreflux continued for 24 hours.

The cooled solution was diluted with ethyl acetate, washed with water,aqueous sodium bicarbonate, and then with water until neutral.

The organic solution was dried with sodium sulfate, evaporated todryness, and the product crystallized from methylene chloride-hexane,thus furnishing 3-methoxy-17- acetoxy-A -estrapentaene.

Example II 1 g. of 3-methoxy 17-acetoxy-A -estrapentaene was treatedfollowing the procedure described in Example II, except thatN-bromosuccinimide was substituted by N-chlorosuccinimide, thusaffording B-methox -16ot-chloro-A -estratetraen-17-one.

Example IV I 1 g. of 3-methoxy-17-acetoxy-A -estrapentaene was treatedin accordance with Example II with the exception that N-bromosuccinimidewas substituted by N-iodosuccinimide, thus giving 3 -methoxy-16a-iodo-43 -estratetraen-17-one.

7 Example V A solution of g. of 3-methoxy-16tx-iodo-Aestratetraen-17-one in 125 cc. of acetonitrile was refluxed for 16 hoursin a Soxhlet apparatus containing 25 g. of silver fluoride. The mixturewas cooled to room temperature, the suspended silver salts filtered oiland the filtrate diluted with 250 cc. of chloroform. The resultingsolution was Washed with water, dried over sodium sulfate and evaporatedto dryness. The residue upon chromatography and recrystallization of thesolid fractions yielded pure 3-methoxy-16fi-fluoro-Aestratetraen-l7-one.

Example VI To a solution of 2 g. of 3-methoxy-16a-bromo- A-estratetraen-17-one in cc. of dimethylformamide were added 7 g. oflithium bromide and the resulting mixture was stirred at roomtemperature for 24 hours. The solution was diluted with Water, theformed precipitate separated by filtration and recrystallized frommethanol thus yielding I 3-methoxy-16fi-bromo-A -estratetraen-l7-one.

' Example VII 3 methoxy-16a-iodo-A -estratetraen-17-one was treated inaccordance with Example VI, but using lithium chloride instead oflithium bromide, furnishing 3-methoxy-16,B-chloro-A-estratetraen-17-one.

Example VIII 3-methoxy-16a-bromo-A -estratetraen-l7-one was treatedaccording to Example VI, except that lithium bromide was substituted bylithium chloride thus giving 3-methoxy-16fl-chloro-A-estratetraen-l7-one.

Example IX 3 methoxy-16a-iodo-A -estratetraen-17-one was treated by thetechnique described in Example VI, except that lithium bromide wassubstituted by lithium fluoride to produce 3-methoxy-16fl-fluoro-Aestratetraen-17-one.

Example X A -dehydroestrone (Magerlein et al. v. supra) was successivelytreated in accordance with Examples I and II, producing respectively3,17-diacetoxy-A estrapentaene and 3 acetoxy 16 -bromo-Aestratetraen-17-one.

Example XI 3,17-diacetoxy-A -estrapentaene was treated in accordancewith Examples III and IV giving respectively 3-acetoxy-16a-chloro-A-estratetraen-17 one and 3-acetoxy-16a-iodo-A -estratetraen-17- one.

Example XII Example XIII A solution of 5 g. of 3-methoxy-16ot-bromo-A-estratetraen-17-on'e' in' 250 cc. of thiophene-free benzene was treatedwith 27.5 cc. of 4N methylmagnesium bromide in ether and -the mixturerefluxed with the exclusion of moisture for 3 hours. The cooled mixturewas cautiously treated with'excess aqueous ammonium chloride solutionand the product isolated by ethyl acetate extraction. The extract waswashedwith water, dried over anhydrous sodium sulfate and evaporated todryness.

Recrystallization from 'rnethylene chloride-hexane alfordedS-methoxy-16rx-bromo-17amethyl-A estratetraen-17,B-ol.

Li LLUUMIEAI starting compounds underl, thus giving the correspondingproducts under II.

Example XI V A solution of 1 g. of 3-methoxy-16a-bromo-A 9-estratetraen-17-one in 30 cc. of anhydrous benzene was added, undernitrogen, to a solution prepared by dissolving 1.4 g. of potassium in 30cc. of t-amyl alcohol. A slow current of purified acetylene was passedthrough the solution for 40 hours, whereupon the solution was dilutedwith water and extracted with benzene. The organic extracts were thenwashed to neutral and dried over anhydrous sodium sulfate. Evaporationof the solvent and chromatography of the residue on 70 g. of alkalinealumina gave in the hexane-benzene (2:3) fractions a product, which uponrecrystallization from acetone hexane afforded the pure3-methoxy-16a-bromo-17wethinyl-A -estratetraen-17,8-01.

Using exactly the'same conditions there were treated the startingcompounds under I, thus yielding the corre-.

' spending products under H.

3-methoxy-16a-ch1oro-A 3 (ll) estratetraen-U-one. 3-meth0xy-16a-iodo-Aestratetraen-17-one. 3-methoxy-ltia-fluoro-A J (11) estratetraen-17-one.3-methoxy-16B-iodo-A (10) A? (11) estratetraen-17-one.3-111eth0xy-1(id-bromo-A estratetraen-17-one. 3-methoxy-16B-chloro-A 3estratetraen-U-one. 3-methoXy-l6B-fluoro-A (11) estratetraen-lfione.3-acetoxy-l6a-bromo-A 9 J? (11) estratetraen-17-one.

estratetraen-17one.

Example XV A'solution of 1 g. of 3-'nethoxy-16a-brorno-l7a-ethinyl-' wasdissolved in ethyl acetate, the organic solution washed with dilutehydrochloric acid and water to neutral, dried and evaporated to dryness.Recrystallization from aceestratetraen-HB-ol.

By the same procedure, the rest of the final compounds of Example XIVwere converted into the corresponding 170t-Vllly1 derivatives.

6. Example XVI A solution of l g. of sodium borohydride in 3 cc. ofwater was added to an ice-cooled solution of l g. of3-methoxy-16a-bromo-A -estratetraen 1 7 one in 120 cc. of methanol andthe mixture was allowed to stand for 16'hours at room temperature. Theexcess reagent was decomposed by addition of acetic acid, the solutionconcentrated to small volume in vacuo and diluted with water. 7 Theproduct was extracted with ethyl acetate, the extract was washed withwater, dried and evaporated. The solid residue was purified bycrystallization from acetone-hexane to give 3-methoxy-16u-bromo-Aestratetraen-17B-ol.

Following the above procedure there were treated the starting compoundsunder I, to produce the products under II. t

B-methoxy-lGa-chloro-A estratetraen-17-oue.

3-methoxy-l6a-iodo-A m( estratetraen-17-one.

estratetraen-l7-one. 3-methoxy-16B-iodo-A ,3 (l1)- estratetraen-17-one.3 methoxy-lfidbromo-A M (10) estratetraen-l7-one.

.3-methoxy-16B-ehloro-A 3.5(10),9 (u).

estratetraen-17-one. 3-methoxy-16fl-fluoro-A .3 (l1)-estratetraen-l7-one. 3-aeetoxy-16a-bromo-A 3 9 (11)- estratetraen-U-one.3-acetoxy-16a-ehloro-A (1W1 (11)- estratetraen-l7-one.

3-methoxy-16a-ehlo 1.as (10mm).

estratetraen-HB-ol. 3-methoxy-16weh1oro-A (11)- estratetraen-UB-ol.3-methoxy-16a-fluoro-A (10) J (11)- estratetraen-l? -o1.

I 3-methoxy-16B-iodo-A1.51.: (1o) .0 (u)- estratetraen-flfl-ol.3-methoxy-16B-bromo-A ,8 .5 (in) mm).- .estratetraen-Ufl-ol.3-methoxy-165-chloro-A (l1)- estratetraen-HB-ol. 3-methoxy-16B-fluoro-Aestratetraen-UB-ol. lfia-bromo-A ,3

estratetraen-3,17fi-dio1. 16 1 1 3! .3 .a (10) .0 (11)..

estratetraen-3,17fl-dio1.

Example X VI] Example XVIII The starting compounds of Example XVII weretreated by the procedure described in that example, except that aceticanhydride was substituted by propioni c, anhydride,

caproic anhydride and cyclopentylpropionic anhydride,

7 thus yielding respectively the corresponding propionates,

caproates and cyclopentylpropionates of said starting compounds. iExample XIX To a solution of 5 g. of 3-methoxy-16a-bromo-17amethyl-M-estratetraen-175-01, in cc. of anhydrous benzene there were added 1 g.of p-toluenesul- By the same procedure there were treated the startingcompounds under I, to produce the corresponding products under H.

3methoxy-16a-chloro-17a-methyl- A1 5 -estratetraen-Ufipl.

B-methoxy-lfifi-chloro-lM-ethinyl- A -estratetraen-lm ol.

The propionate 0t 3-methoxy-l6a- Erample XX The starting compounds ofExample XVIII were treated in accordance with that example, but usingcaproic anhydride and undecenoie anhydride instead of propio-nicanhydride, thus giving respectively the corresponding caproates andundecenoates of said starting compounds.

Example XXI wherein X is a halogen; .R is a member of the groupconsisting of hydrogen, a lower alkyl and a hydrocarbon carboxy lic acylgroup of less than 12 carbon atoms; R

is selected from the group consisting of hydrogen and a hydrocarboncarboxylic acyl group of less than 12 carbon atoms; R is a member of thegroup consisting of hydrogen, lower alkyl, lower alkenyl and loweralkynyl.

2. 3-methoxy a bromo-17-a-methyl-A estratetraen-17fl-ol.

3. S-methoxy 16cc chloro-17a-methyl-A estratetraen-UB-olQ .4. 3-methoxy16a fluoro-17a-methyl-A estratetraen-NB-ol.

5. 3-methoxy 16B fluoro-17a-methy1-A estratetraen-17fl-ol.

7.. B-methoxy 16,8 bromo-17a-methyl-A estratetraen-17,8-ol.

8. 16ot-br0mo -17ot methyl-A -estratetrae 3,17,8-dio1.

9. 160t-Chl0l'0 17a methyl-A -estratetraen- 3,17 8-diol.

10. 3-rnethoxy 16a bromo-17a-ethynyl-A estratetraen-17B-o1.

1 1. 3-methoxy 16cc chloro-17u-ethynyl-A estratetraen-lYB-ol.

14. 3-rnethoxy 16,8 chloro-17a-ethynyl-A estratetraen-17fi-ol.

15. 3-methoxy 16,8 bromo-17u-ethynyl-A estratetraen-17B-ol. 16. Acompound of the following formula:

no RO I H;

References Cited in the file of this patent UNITED STATES PATENTS Hogget a1; May 5, 1959 Reimann et a1. Feb. 5, 1963 OTHER REFERENCESMagerlein et al.: J.A.C.S.' 80, 2220 (1958). Mueller et al.: J. Org.Chem. 26 2403 (July 1961).

16. A COMPOUND OF THE FOLLOWING FORMULA: